Enhancement of stent radiopacity using anchors and tags

ABSTRACT

A stent system is disclosed which comprises a stent made of a conventional metal alloy, such as stainless steel, treated with chains of peptides (“anchors”) which comprise functionality to bind to the metal surface and to bind to other peptides (which other peptides are termed “recognition” peptides) and recognition peptides, which comprise one end which binds to (“recognizes”) the anchor peptide and one end which is bound to a radiodense dye, which system enhances radiopacity relative to the stent alone.

FIELD OF THE INVENTION

[0001] The present invention generally relates to medical devices,particularly stents and covered stents. More particularly, the presentinvention is directed to stents with enhanced radiopacity generated bythe use of anchors and tags.

BACKGROUND OF THE INVENTION

[0002] Blood vessels in the body may become narrowed, and the flow ofblood impeded. Such a condition is referred to as a stenosis or astenotic condition. One way of alleviating problems associated with thestenosis is to insert a stent to help widen the narrowed passage bysupporting the walls of the vessel to keep it open.

[0003] In placement and monitoring of the stent, it is desirable to beable to visualize the position of the stent within the body. A typicalmethod of visualization is fluoroscopy, which involves the use of acontinuous x-ray beam in real time with live images being displayed on amonitor. Although representative stents are made of stainless steel,which generally can be visualized by x-rays, the small dimensions ofstents, particularity coronary stents, are such that there is difficultyin visualizing the stents via fluoroscopy. The present invention isdirected to a stent system wherein the ability to visualize the stent inthe body by a technique such as fluoroscopy is enhanced. To fullyappreciate the scope of the invention, background on stents is provided.

[0004] Generally, stents, grafts, and graft stents are implantablemedical devices (sometimes termed implantable tubular prostheses) whichare placed within blood vessels and other body passageways to treatdisease conditions such as stenoses, occlusions, and aneurysms.Transluminal implantation of such devices requires that they beintroduced to the site collapsed about or within an introduction deviceand released to self expand or are expanded by other mechanisms to anexpanded tubular state providing a lumen of approximately the same sizeas the patent vessel or duct lumen.

[0005] Typically, stents are made from a metal alloy, such as, but notlimited to, stainless steel, and have a hollow tubular shape. To meetrequirements for medical use, more fully discussed below, the stentshave an open lattice-like structure, in which the individual metalcomponents, such as struts, have a diameter or thickness of 0.003″ orless. This small dimension renders the strut difficult to detect intechniques employing x-radiation (“x-rays”), such as fluoroscopy.

[0006] Scattering of x-rays is approximately proportional to the squareof atomic number, so that materials of atomic number higher than thecomponents of the metal alloy of the stent would enhance scattering, anddetectability. However, higher atomic number materials tend to be moreexpensive and more difficult to fabricate than stainless steel. Oneapproach is to coat the stent, comprising a typical metal alloy such assteel, with a metal of higher atomic number. However, there are concernsassociated with corrosion through galvanic effects. The presentinvention is directed to a stent system which has enhanced radiopacityby the use of “anchors” to the metal surface (which anchors are chainsof peptides that adhere to the metal implant surface) and tags (which isconnected to the anchor and which achieve high contrast in thevisualization medium employed). Such a system employing anchors and tagsdoes not manifest corrosion through galvanic effects. Before discussingthis further, a review of stent use and construction is provided.

[0007] When the body lumen is weakened, for example, dissectional arterylining occurs in a body lumen such as a blood vessel, the weak part ofthe body lumen might collapse to occlude a fluid passageway. To preventsuch an occlusion, a stent is implanted within the blood vessel tosupport the blood vessel from the inside thereof. Namely, a stent isdelivered to a desired location in the blood vessel, and expanded in acircumferential direction in the blood vessel to support and maintainthe patency of the blood vessel. Using the stent to support the bloodvessel can avoid surgical exposing, incising, removing, replacing orbypassing a defective blood vessel required in the conventional vascularsurgery.

[0008] Stents can be viewed as scaffoldings, of generally cylindricalsymmetry, that function to physically support, and, if desired, expandthe wall of the passageway. Typically, a stent consists of two or morestruts or wire support members connected together into a lattice-like oropen weave frame. Most stents are compressible for insertion throughsmall cavities, and are delivered to the desired implantation sitepercutaneously via a catheter or similar transluminal device. Once atthe treatment site, the compressed stent is expanded to fit within orexpand the lumen of the passageway. Stents are typically eitherself-expanding or are expanded by inflating a balloon that is positionedinside the compressed stent at the end of the catheter. Intravascularstents are often deployed after coronary angioplasty procedures toreduce complications, such as the collapse of arterial lining,associated with the procedure.

[0009] There have been introduced various types of stents, and they canbe typically categorized from viewpoints of methods for expanding thestent, shapes, methods for manufacturing the stent, designs and so on.From a viewpoint of methods for expanding the stent, stents can becategorized as a self-expandable stent which can be expanded by itself,and a balloon expandable stent. In the balloon expandable stent, thestent is mounted on an expandable member, such as a balloon, provided ona distal end of an intravascular catheter, and the catheter is advancedto the desired location in the body lumen to deliver the stent. Then,the balloon on the catheter is inflated to expand the stent into apermanent expanded condition, and the balloon is deflated for removingthe catheter from the stent.

[0010] From a viewpoint of materials, stents can be categorized into atubular stent and a wire stent, and from a viewpoint of methods formanufacturing the stent, stents can be categorized as an etched stentand a laser cut stent. Then, from a viewpoint of designs, stents can becategorized into numerous types, but roughly, stents can be categorizedinto a stent having a “coil” pattern on the surface thereof, and a stenthaving a mesh or “ring” pattern on the surface thereof.

[0011] Palmaz describes a variety of expandable intraluminal vasculargrafts in a sequence of patents; e.g., U.S. Pat. Nos. 4,733,665;4,739,762; 4,776,337; and 5,102,417. The Palmaz '665 patent describesstents that are expanded using angioplasty balloons. The stents arevariously a wire mesh tube or of a plurality of thin bars fixedlysecured to each other. The devices are installed, e.g., using anangioplasty balloon and consequently are not seen to be self-expanding.The Palmaz '762 and '337 patents describe the use of thin-walled,biologically inert materials on the outer periphery of theearlier-described stents. Finally, the Palmaz '417 patent describes theuse of multiple stent sections each flexibly connected to its neighbor.

[0012] In all types of stents, the stent expands from an initialdiameter to a larger diameter so as to be suitable for a particular sizeof the targeted body cavity. Therefore, the stent must haveexpandability in the circumferential direction. Also, since the reasonthe stent is placed in the body lumen is to support a cavity walltherein to maintain the patency thereof, it is very important that thestent has radial strength as well as support capability.

[0013] At the same time, since the stent is generally delivered throughtortuous path to the desired location in the body lumen, the stent musthave flexibility in the axial direction. Namely, the stent must beflexible and is bent easily to thereby facilitate the delivery of thestent in the narrow and meandering body lumen.

[0014] In the aforementioned various types, since simply bending a wireforms a wire stent, this makes the wire stent not only expanded easily,but also shrunk easily. Namely, the wire stent does not have supportcapability for maintaining the expanded condition in order to keep thebody lumen open. On the other hand, a tube type stent has enough supportcapability to maintain its expanded condition for holding the body lumenopen.

[0015] The present invention is directed to a stent system which allowsthe use of lower cost, more easily fabricated, stents, which are lessradiodense, in conjunction with materials which are more radiodense,thereby allowing greater visualization in vivo during catheterintroduction into the vessel, stent deployment, and post-operativediagnosis. Accordingly, an object of the invention is to provide a stentsystem which is sufficiently radiopaque, flexible, has a low profile, issubstantially non-thrombogenic, and which will eliminate corrosion.

[0016] Another object of the invention is to provide an external surfacein the stent system that is both biocompatible and sufficientlyscattering to x-rays that the stent system is easily visualized usingtechniques such as fluoroscopy.

[0017] Another object of the present invention is to minimize galvaniccorrosion between dissimilar metals.

[0018] Basic background material may be found in H. Lodish, et al.,Molecular Cell Biology, 3^(rd) edition, Scientific American Books 1995and A. Guyton and J. Hall., Textbook of Medical Physiology, 9^(th)edition, W. B. Saunders.

SUMMARY OF THE INVENTION

[0019] The present invention is generally directed to a stent systemwhich comprises a material more radiopaque than the metals typicallyused to manufacture stents (“the radiodense material”), which radiodensematerial is placed within the stent system in such a way as to minimizeor reduce corrosion problems associated with galvanic effects. Galvaniceffects in the stent system can be minimized by coating the metal of thestent with a material which is not electronically conducting. Theradiodense material can be coated onto the non-electronically conductingmaterial.

[0020] One embodiment of the present invention is a stent systemcomprising a stent manufactured of a metal alloy, such as stainlesssteel, treated with chains of peptides that adhere to the metal alloysurface (denoted “anchors, wherein each anchor peptide has a free endwhich “recognizes” (i.e., binds) a “recognition” peptide), with thechains of peptides treated with recognition peptides, wherein one end ofthe recognition peptide entity is attached to a dye molecule (“tag”) andthe other end is bound by the free end of the anchor peptide.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021]FIG. 1. Is a perspective view of a stent; and

[0022]FIGS. 2 and 3 are schematic diagrams of the anchor and tab systemof the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0023] When designing endovascular medical devices (i.e., stents) thereis often a need for adequate visualization (e.g., radiopacity). In thearea of stents, it is often necessary to be able to visualizeimplantable medical devices using a fluoroscope, which employs x-rays.The ability to visualize via x-rays depends both on the scattering powerof the material in the stent (scattering power going roughly as thesquare of the atomic number of the element; x-ray absorption alsoincreasing with atomic number) and the amount of the material (thethicker the material, the more easily visualized). As the density andthickness of a material increase, so does the radiopacity. However, in amove toward less invasive techniques, the thickness of a given componentof a stent is limited. Further, with conventional metal alloys (e.g.stainless steel) at the dimensions used for stents (e.g., less than0.003 inches), there is difficulty in visualizing stents in fluoroscopy.

[0024] The present invention discloses a method to enhance theradiopacity of stents and a stent system formed from the method. Themethod to form the stent system involves first treating a conventionalstent comprising metal with an anchoring entity, which anchoring entitymay comprise chains of peptides that adhere to the metal of the stentand second treating the stent, comprising the anchoring entity, with arecognition peptide, which recognition peptide is capable of binding tothe anchoring entity and which recognition peptide comprises a tag whichcomprises a dye or contrast medium, which tag enhances the radiopacityof the stent system relative to the stent alone. The stent systemcomprises a stent 10, peptides P adhering to the surface of the stent(“anchors”) which peptides comprise a recognition site R capable ofbinding to recognition peptides RP, and recognition peptides which areboth bound to the anchors and which comprise a dye which enhances theradiopacity of the stent system relative to the stent.

[0025] In more detail, in anchor/tag visualization, a metal stent istreated with “anchors” (chains of peptides that adhere to the metalimplant surface). The “tag” is a dye/contrast medium which is treatedwith recognition peptides (one end of a given recognition peptide isattached to the dye molecule and the other end is “recognized” (i.e.,bound) by the free end of the anchor peptide. Essentially, the openbinding sites on the anchor and tag are sterogenic, exactlycomplementary by geometry, and bind with high specificity and affinity(in a similar way to an antibody/antigen mechanism). The adhesion of theanchor to the stent (“implant”) is important to the visualization of thestent under fluoroscopy because it allows for a place for the dyerecognition peptide complex to bind. Once access to the vascalature isgained, the stent is highly radiopaque as the physician checks theprogress of the stent to the site of the lesion.

[0026] The present invention allows for more exact stent placementthrough better radiopacity introduced through the tag. The anchorpeptides and recognition peptides are biocompatible and degradable.Further, as the peptide-dye complex degrades, it is readily absorbableand would not cause micro-emboli or a foreign body encapsulationresponse.

[0027] In alternate embodiments, the anchor peptides and recognitionpeptides could be introduced at the same time or could be introduced atdifferent times.

[0028] In an alternate embodiment, the number of tags delivered does notcorrespond exactly to the number of anchors available.

[0029] In an alternate embodiment, the anchor peptides may release thetags without themselves becoming dislodged from the device or losingfunctionality.

[0030] The present anchor/tag invention presents advantages over theprior art. The method of the present invention gives physicians analternative when viewing stents under fluoroscopy. The anchor/tag methodof intermittent stent visualization overcomes the traditional barriersof radiopacity, density, and mass of stent material. Past alternatemethods of radiopacity have included metallic coatings on stents whichboth increase the mass and which present corrosion problems. The presentmethod is unique in that impart radiopacity to the device, potentiallytemporarily and potentially with the ability to degrade over time. Inthose situations wherein degradation has occurred, the stent can be maderadiopaque at a later time. Further, the device can be manufactured withanchor peptides only and then dipped in a solution with the recognitionpeptide/tag complex at a later time and prior to the medical procedure.

[0031] In an alternate embodiment, the recognition peptide/dye complexis degradable over time and/or has the ability to release from theanchor, with the anchor retaining the ability to reattach to another tagcomplex, if the other tag complex were introduced.

[0032] In an alternate embodiment, proteins could release the tags in afew days (for example, two days), correlating to when the patient isreleased from the hospital. At the time of followup (for example, sixmonths later), the physician could deliver a local bolus of radiopaquetag solution endovascularly, which would bind to anchor peptides. Thisprocess can be repeated multiple times until device becomes completelyencapsulated by the body.

[0033] Relevant to prior art stent coatings, the anchor/tag method ofstent visualization is not constrained by the density and mass of stentmaterial as in traditional approaches to stent visualization. Currentalternate methods include the use of metallic coatings on stents toenhance radiopacity. However, metallic coatings often rely on the use ofdissimilar metals, which may result in a galvanic effect releasingmetallic ions into the blood stream and surrounding tissues.

[0034] This proposed anchor/tag method is novel in that it does not relyon dissimilar metals and uses naturally occurring amino acids. Proteinshave enhanced biocompatibility. Proteins also lend themselves toendothelialization and promote healing at the site of implantation. Theuse of this invention to enhance radiopacity results in a lower profile(i.e., through reduced wall thickness) and more flexible stents. Thus,the amount of material needed to make a stent adequately visible underfluoroscopy can be reduced.

[0035] The present invention has further embodiments. The stent could bealternatively treated on inside diameter, outside diameter, or bothdiameters, depending on the level of radiopacity desired. Different dyesand anchors could be used for different applications (for example,biliary, arterial, venus, etc.) depending upon tissue morphology. Thetreatment or coating can be placed on the device prior to sterilizationand packaging or as a part of the procedure. For example, the cliniciancould submerge the device in one solution to attach anchor peptides andthen a second solution for attachment of the recognition peptide-dyecomplex. Alternatively, the stent could be provided pre-coated withanchor peptides and the clinician could submerge in solution containingtags. The intermittent radiopacity can be classified into three, roughlydefined, categories: short term (e.g., two days), mid-term (e.g., onemonth) and long term (e.g., six months).

[0036] Although many embodiments of this invention pertain to treatmentof metallic stents to enhance radiopacity to x-rays, the invention scopespans enhancement of visualization of both metallic and non-metallicmedical devices to x-ray radiation and/or other radiations. The basicconcept is to tag the device with a probe showing enhanced sensitivityto a given visualization device.

[0037] The anchor/tag method of stent visualization of the presentinvention is related to work in immuno-fluorescence, although theimmuno-fluorescence work involves different wavelengths of observationand different means of visualization.

What is claimed is:
 1. A stent system which comprises a metallic stenttreated with anchor chains of peptides which bind to the metal surfaceand recognition peptides, which comprise one end which binds to theanchor peptide and one end which is bound to a radiodense dye.
 2. Thestent system of claim 1 wherein the metal is stainless steel.
 3. A stentsystem which comprises a metallic stent treated with chains of peptides,which bind to the metal surface and to other peptides.
 4. A method offorming a stent system with enhanced visualization in fluoroscopycomprising the steps of: treating a metallic stent with anchoringpeptides which are capable of adhering to the metal surface and arefunctionality capable of binding to other peptides; treating a metallicstent treated with the anchoring peptides with recognition peptides,which recognition peptides are functionality capable of binding to theanchoring peptides and capable of binding to radiodense dyes.
 5. Amethod of forming a stent system with enhanced visualization comprisingthe steps of: treating a stent with anchoring peptides which arefunctionality capable of adhering to the stent surface and to otherpeptides, termed recognition peptides.
 6. The method of claim 5 furthercomprising treating the stent comprising anchoring peptides withrecognition peptides which both bind to the anchoring peptide and whichcomprise an element which causes enhanced visualization relative to thestent alone.